nitroarginine and Cardiomegaly

To explore the changes in adrenomedullin (ADM) and receptor activity-modifying protein 2 (RAMP2) mRNA in myocardium and vessels in hypertension, a hypertensive rat model was prepared by administering L-NNA. Contents of ADM in plasma, myocardium and vessels were measured by radioimmunoassay (RIA). The levels of pro-ADM mRNA of myocardium and vessels were determined by competitive quantitative RT-PCR. The results showed that L-NNA induced hypertension and cardiomegaly. The ratio of heart to body weight increased by 35.5% (P<0.01). In hypertensive rats the ir-ADM in plasma, myocardium and vessels was increased by 80%, 72% and 57% (P<0.01), respectively compared with the control. The amounts of ADM mRNA in myocardium and vessels were increased by 50% and 109.2% (P<0.05), respectively, and the amounts of RAMP2 mRNA was increased by 132% and 87% (P<0.01), respectively, compared with control. The levels of ADM in myocardium and vessels were positively correlated with RAMP2 mRNA, the correlation coefficients were 0.741 and 0.885 (P<0.01), respectively. The results obtained indicate that in hypertensive rats, ADM is elevated in plasma, myocardium and ves-myocardium and vessel, and ADM and RAMP2 mRNA are up-regulated in myocardium and vessel. The ADM/RAMP2 system may play an important role in the pathogenesis of hypertension.

Topics: Adrenomedullin; Animals; Cardiomegaly; Hypertension; Myocardium; Nitroarginine; Rats; Receptor Activity-Modifying Protein 2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

A rat aortic banding model of cardiac hypertrophy was used to test the hypothesis that reversible inhibition of mitochondrial respiration by nitric oxide (NO*) elicits a bioenergetic defect in the hypertrophied heart. In support of this hypothesis, the respiration of myocytes isolated from hypertrophied hearts was more sensitive to exogenous NO* (IC(50) 200 +/- 10 nM vs. 290 +/- 30 nM in controls, P = 0.0064). Hypertrophied myocytes also exhibited significantly elevated inducible NO* synthase (iNOS). Consistent with this endogenous source for NO*, the respiration of hypertrophied myocytes was significantly inhibited at physiological O(2) tensions versus controls. Both the nonspecific NOS inhibitor nitro-L-arginine and the iNOS-specific inhibitor N-[3-(aminomethyl)- benzyl]acetamidine. 2HCl reversed this inhibition, with no effect on respiration of control myocytes. Consistent with an NO*-mediated mitochondrial dysfunction, the ability of intact perfused hearts to respond to a pacing workload was impaired in hypertrophy, and this effect was reversed by NOS inhibition. We conclude that endogenously generated NO* can modulate mitochondrial function in the hypertrophied heart and suggest that this bioenergetic defect may underlie certain pathological features of hypertrophy.

Topics: Amidines; Animals; Benzylamines; Cardiomegaly; Cell Respiration; Energy Metabolism; Enzyme Inhibitors; Male; Mitochondria; Muscle Fibers, Skeletal; Myocardial Contraction; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitroarginine; Oxidative Phosphorylation; Rats; Rats, Sprague-Dawley

Chronic nitric oxide synthase (NOS) inhibition results in hypertension and myocardial injury. In a rapid and severe model of chronic NOS inhibition, we determined the role of angiotensin II in these effects by using angiotensin II receptor blockade and by measuring cardiac angiotensin II concentrations before and during development of cardiac damage. Rats received either no treatment, the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 500 mg/l), the angiotensin AT(1) receptor antagonist losartan (400 mg/kg chow), or L-NNA plus losartan for 21 days. In the second protocol, five groups of rats received L-NNA (500 mg/l) for 0, 4, 7, 14 and 21 days, respectively. L-NNA increased systolic blood pressure (SBP) (227+/-8 versus 143+/-6 mm Hg; P<0.01), heart weight index (0.44+/-0.02 versus 0.32+/-0.01; P<0.01) and induced coronary vasculitis and myocardial necrosis. Co-treatment with losartan prevented all changes. L-NNA during 4 days decreased cardiac angiotensin II (23+/-4 versus 61+/-15 fmol/g; P<0.05). Although after 7 days, fresh infarcts and after 14 days organized infarcts were present, cardiac angiotensin II was only slightly increased after 21 days (100+/-10 fmol/g; P<0.05). In conclusion, losartan-sensitive cardiac damage due to chronic NOS inhibition is not associated with primary increase of cardiac angiotensin II, suggesting that chronic NOS inhibition increases cardiac sensitivity for angiotensin II.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart; Losartan; Male; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Vasculitis

1. The effect of chronic ischaemic myocardial remodelling on small coronary artery reactivity in vitro was studied in a newly developed pig model. 2. Pigs were subjected to selective intracoronary embolizations with microspheres in the left anterior descending artery and circumflex artery causing scattered myocardial fibrosis. After an observation period of 130 days, heart dimensions and ejection fraction were determined with magnetic resonance imaging. Small arteries were isolated from the left ventricle and mounted as ring preparations in a myograph. Control arteries were taken from matched non-embolized pigs. 3. Compared with control pigs, end-systolic and diastolic volumes increased and left ventricular mass nearly doubled in embolized pigs. This indicates substantial myocardial hypertrophy, as the fraction area of fibrosis was only 12%. 4. Coronary small arteries preconstricted with 30 mmol/l KCI showed a normal contractile response to acetylcholine and 5-hydroxytryptamine. Sensitivity of the relaxation to bradykinin was nearly 3-fold increased and also slightly enhanced to isoprenaline in arteries from embolized pigs compared with controls, whereas relaxation to 5-hydroxytryptamine in the presence of ketanserin was similar. After inhibition of nitric oxide synthase with NG-nitro-L-arginine the sensitivity to acetylcholine increased to a similar extent in arteries from embolized pigs and controls. NG-Nitro-L-arginine abolished the relaxing effects of bradykinin and of 5-hydroxytryptamine in the presence of ketanserin. 5. We conclude that both the contractile function of the smooth muscle cells and the endothelial production or action of nitric oxide is preserved or slightly enhanced in coronary small arteries from pigs with chronic myocardial remodelling.

Topics: Acetylcholine; Animals; Bradykinin; Cardiomegaly; Cardiotonic Agents; Chronic Disease; Coronary Vessels; Drug Synergism; Endothelium, Vascular; Isoproterenol; Ketanserin; Models, Biological; Myocardial Ischemia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Serotonin; Serotonin Antagonists; Swine; Vasoconstrictor Agents

1. Recent evidence suggests that nitric oxide (NO) modulates the contractile force of isolated cardiomyocytes in a biphasic manner. We sought to examine whether myocardial hypertrophy induced by long-term hypertension changes the effects of NO on myocardial contractility. 2. We used constant flow perfused non-paced Langendorff preparations of hearts of 3 months old Wistar rats (WIS, n = 23) and of stroke-prone spontaneously hypertensive rats (SHR) at the age of 10 months (SHR10, n = 16) and 15 months (SHR15, n = 8). Changes of left ventricular peak pressure (LVP), +dP/dt(max), -dP/dt(max), coronary perfusion pressure (CPP) and heart rate (HR) were recorded after infusion of noradrenaline (NA, 0.1 micromol l(-1)), glyceryl trinitrate (GTN, 1-100 micromol l(-1)), S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1-10 micromol l(-1)) and N(omega)-nitro-L-arginine (L-NOARG, 0.1-1 mmol l(-1)). 3. Long-term hypertension induced myocardial hypertrophy and an abnormal response to NA. The relative heart weight (in mg kg(-1)) increased from 2.95 +/- 0.04 (WIS) to 6.67 +/- 0.34 (SHR15), while the increase in +dP/dt(max) induced by NA was absent in SHR15. Hearts of SHR10 showed an intermediate response. 4. Both SNAP and GTN significantly increased LVP, +dP/dt(max) and -dP/dt(max) in hearts of WIS and of SHR. In WIS but not in SHR10, SNAP also increased HR. In SHR10 the lowest concentration of SNAP (1 micromol l(-1)) showed no effect on contractility but a significantly diminished reduction of CPP suggesting inactivation of extracellularly released NO in the coronary circulation of SHR. 5. L-NOARG significantly reduced contractility in hearts of WIS and of SHR to a similar extent. At a concentration of 1 mmol l(-1) L-NOARG also reduced HR. 6. These results suggests that positive inotropic effects of exogenous and endogenous NO are not changed in hypertension induced myocardial hypertrophy.

Topics: Animals; Blood Pressure; Cardiomegaly; Heart; Heart Rate; Hypertension; In Vitro Techniques; Male; Myocardial Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; Norepinephrine; Penicillamine; Rats; Rats, Inbred SHR; Rats, Wistar; S-Nitroso-N-Acetylpenicillamine; Stimulation, Chemical; Vasoconstrictor Agents; Vasodilator Agents; Ventricular Pressure

To examine whether the bradykinin-nitric oxide (NO) pathway directly participates in the antihypertrophic property of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure, the effects of bradykinin were studied in rat cultured heart cells. Bradykinin (0.1, 1 nM) prevented the phenylephrine-induced increase in protein/DNA content, an index of hypertrophy of heart cells, and amplified the nitrite/nitrate content in the medium. Perindoprilat (1 microM), an ACE inhibitor, also restrained the progression of cardiac hypertrophy and augmented NO release. These effects of perindoprilat were abolished by HOE-140 (kinin B2 antagonist), N omega-nitro-L-arginine (NO synthase inhibitor), and methylene blue (guanylate cyclase inhibitor). Furthermore, there was a significant correlation between protein/DNA content and nitrite/nitrate content. These results indicate that bradykinin inhibits the progression of cardiac hypertrophy due to the increase in NO release and that perindoprilat produces beneficial effects on cardiac hypertrophy by stimulating the bradykinin-NO pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Bradykinin; Bradykinin Receptor Antagonists; Cardiomegaly; Cells, Cultured; Heart; Indoles; Myocardium; Nitrates; Nitric Oxide; Nitrites; Nitroarginine; Phenylephrine; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Regression Analysis